Combined modality therapy with chemotherapy and radiation has been frequently used in treating various kinds of human cancers. There are at least three major advantages to combine chemotherapy with radiation therapy for treating cancers. First, by offering systemic control over metastatic disease, chemotherapy complements radiation therapy's pivotal role in providing local control over the primary tumor.
Second, chemotherapy may contribute in local control by reducing the chemo-sensitive subpopulation of the primary tumor. Third, some chemotherapeutic drugs can enhance the cytotoxic effect of low-LET (linear energy transfer) radiation (such as photons and electrons), and therefore, improve the treatment efficacy toward the irradiated tumors. Indeed, numerous randomized clinical trials, conducted in various clinical settings, have shown a superior treatment efficacy of combination chemoradiation than either modality alone. However, the efficacy of various chemoradiation regimens is still largely limited by the cumulative normal tissue toxicity from combining two modalities.
A better understanding of the mechanism of cytotoxic interaction between chemotherapy and radiation and the development of new drugs that can enhance radiation cytotoxicity selectively toward cancer cells are among the major challenges for cancer researchers.
The catalytic activity of DNA topoisomerase I (TOP1) is important for many aspects of nucleic acid metabolism including DNA replication elongation, transcription elongation of RNA and regulation of DNA supercoiling. Mammalian TOP1 is also a major cellular target of an increasing number of anticancer drugs, including camptothecin derivatives, DNA minor groove-binding drugs such as Hoechst 33342 and nogalamycin, and indolocarbazole (INDO) derivatives.
Instead of direct inhibition of catalytic enzyme activity, TOP1 drugs kill cells by converting an essential DNA topology modifying activity into a DNA breaking poison, which damages DNA through interactions with cellular processes such as replication of DNA. The presence of elevated TOP1 levels in both proliferating and quiescent tumor cells has rendered TOP1 a favored selective target for anticancer therapy.
INDO derivatives represent a new class of TOP1 drugs. A number of INDO derivatives have been demonstrated to exert their cytotoxic effects through the TOP1-mediated mechanism similar to that of the camptothecin derivatives. Also, based on its cross-resistance toward a camptothecin-resistant mutant TOP1, the INDO derivative R-3 has been proposed to share common steric and electronic features with camptothecin (Bailly, C., et al., Biochemistry, 38:8605–8611, (1999)). However, many INDO derivatives interact with DNA with a higher affinity than camptothecin derivatives (Yoshinari, T., Cancer Res., 53:490–494 (1993); Bailly, C., Mol Pharmacol., 53:77–87 (1998); and Bailly, C., et al., Mol Pharmacol., 55:377–385 (1999)). In addition, some structural derivatives of INDO possess other biological activities including inhibitory effects toward protein kinase C (Bailly, C., et al., Mol Pharmacol., 55:377–385 (1999), and Pereira, E. R., et al., J. Med. Chem., 39:4471–4477 (1996)), protein kinase A (Pereira, E. R., et al., J. Med. Chem., 39:4471–4477 (1996)) and TOP1 kinase (Labourier, E., et al., Cancer Res., 59:52–55 (1999); Anizon, F., et al., J. Med. Chem., 40:3456–3465 (1997)); Moreau, P., et al., J. Med. Chem., 41:1631–1640 (1998); and Moreau, P., et al., J. Med. Chem., 42:1816–1822 (1999)). Notably, the inhibitory activity of TOP1 kinase of the INDO derivative R-3 appears to be distinct from its ability to induce TOP1-mediated DNA cleavage (Labourier, E., et al., Cancer Res., 59:52–55 (1999)).
There is a need in the field to develop more agents that are capable of inducing radiosensitization, especially at a non-cytotoxic level.